In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady ...state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.
The study aimed to determine the relationship between physical illness, mental disorder, and the likelihood of suicide attempt among adults aged 15–54 in the United States. Data were drawn from the ...National Comorbidity Survey (
N=8,098), a national probability sample of adults in the United States. Multivariate logistic regression analyses were used to determine the relationship between self-reported physical illness and the likelihood of suicide attempt. Lung disease (OR=1.8 (1.1, 2.7)), ulcer (OR=2.1 (1.3, 3.4)), and AIDS (OR=44.1 (10.5, 185.6)) were each associated with a significantly increased likelihood of suicide attempt, independent of the effects of mental disorders. Consistent with previous studies, the number of physical illnesses was linearly related to an increased odds of suicide attempt (OR=1.3 (1.2, 1.5)). Possible mechanisms for these associations are discussed. These findings call for the inclusion of a range of physical health problems, especially chronic illnesses, in future research on suicide attempts in the population.
Suicidal thoughts and behaviours during antidepressant treatment, especially during the first weeks of treatment, have prompted warnings by regulatory bodies. The aim of the present study is to ...investigate the course and predictors of emergence and worsening of suicidal ideation during tricyclic antidepressant and serotonin reuptake inhibitor treatment.
In a multicentre part-randomised open-label study, 811 adult patients with moderate to severe unipolar depression were allocated to flexible dosage of escitalopram or nortriptyline for 12 weeks. The suicidality items of three standard measures were integrated in a suicidal ideation score. Increases in this score were classified as treatment emergent suicidal ideation (TESI) or treatment worsening suicidal ideation (TWOSI) according to the absence or presence of suicidal ideation at baseline.
Suicidal ideation decreased during antidepressant treatment. Rates of TESI and TWOSI peaked in the fifth week. Severity of depression predicted TESI and TWOSI. In men, nortriptyline was associated with a 9.8-fold and 2.4-fold increase in TESI and TWOSI compared to escitalopram, respectively. Retirement and history of suicide attempts predicted TWOSI.
Increases in suicidal ideation were associated with depression severity and decreased during antidepressant treatment. In men, treatment with escitalopram is associated with lower risk of suicidal ideation compared to nortriptyline. Clinicians should remain alert to suicidal ideation beyond the initial weeks of antidepressant treatment.
EudraCT (No.2004-001723-38) and ISRCTN (No. 03693000).
Recent studies have reported changes in the time patterns of suicide, with reduced seasonality in some European and Asian countries. Anyway conflicting data were reported on the fading of suicide ...seasonality, and in some countries a rising trend was reported.
Harmonic spectral analysis was used to analyze all suicides in Slovenia in the years 1971 to 2002 (14,325 among males; 4350 among females). Analyses of overall changes are based on data aggregated by intervals of 8 years.
In both sexes, seasonal variance accounts for a statistically significant proportion of total variance (36.0% among males; 13.3% among females). Anyway in both sexes the season-attributable variance in the latest interval is considerably lower than in the preceding periods.
Data could not be analyzed according to age or to mental disorder diagnosis, since this information was not available.
The seasonal effect on mortality by suicide is sensitive to change, but its causes seem not to be sex-dependant.
To determine the association between sleep, mental disorders, and suicidal ideation (SI) and suicide attempt (SA) among adults in the community.
Cross-sectional.
National Comorbidity Survey (n = ...8098).
A representative sample of adults in the United States.
Multiple logistic regression analyses were used to determine the association between usual number of hours of sleep during a 24-h period and SI and SA (past 12 months and lifetime). Analyses were adjusted for differences in demographic characteristics and comorbid mental disorders. Additional analyses examined the relationship between hours of sleep and the odds of SA among adults with SI, compared with SI without SA. Short sleep was associated with significantly increased odds of SI (OR 2.5, 95% CI: 1.6-3.9) and SA (OR 3.0, 95% CI: 1.4-6.4), and with SA among those with SI (past 12 months). These associations persisted after adjusting for differences in demographic characteristics and mental disorders, though the links between short sleep and SA among those with SI were no longer statistically significant after adjusting for panic, mood, and substance use disorders.
Short sleep appears to be associated with increased likelihood of SI and SA, independent of the effects of comorbid mental disorders, among adults in the community. Among adults with SI, short sleep is associated with increased odds of SA, and this association seems largely related to the presence of panic attacks, mood, and substance use disorders. Future studies should investigate the nature of these relationships, and whether and how mental health problems may play a role.
Tricyclic antidepressants and serotonin reuptake inhibitors are considered to be equally effective, but differences may have been obscured by internally inconsistent measurement scales and ...inefficient statistical analyses.
To test the hypothesis that escitalopram and nortriptyline differ in their effects on observed mood, cognitive and neurovegetative symptoms of depression.
In a multicentre part-randomised open-label design (the Genome Based Therapeutic Drugs for Depression (GENDEP) study) 811 adults with moderate to severe unipolar depression were allocated to flexible dosage escitalopram or nortriptyline for 12 weeks. The weekly Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, and Beck Depression Inventory were scored both conventionally and in a more novel way according to dimensions of observed mood, cognitive symptoms and neurovegetative symptoms.
Mixed-effect linear regression showed no difference between escitalopram and nortriptyline on the three original scales, but symptom dimensions revealed drug-specific advantages. Observed mood and cognitive symptoms improved more with escitalopram than with nortriptyline. Neurovegetative symptoms improved more with nortriptyline than with escitalopram.
The three symptom dimensions provided sensitive descriptors of differential antidepressant response and enabled identification of drug-specific effects.
To implement and evaluate an educational program for primary care physicians on recognition and treatment of depression and suicide prevention.
The study was conducted in 3 Slovenian neighboring ...regions (Celje, Ravne na Koroskem, and Podravska) with similar suicide rates and other health indicators. All primary care physicians from Celje (N=155) and Ravne na Koroskem (N=35) were invited to participate in the educational program on depression treatment and suicide risk recognition. From January to March 2003, approximately half of them (82 out of 190; educational group) attended the program, whereas the other half (108 out of 190; control group 1) and physicians from the Podravska region (N=164; control group 2) did not attend the program. The prescription rates of antidepressants and anxiolytics before and after the intervention were compared between the studied regions. Also, suicide rates three-years before and after the intervention were compared.
From 2002 to 2003, there was a 2.33-fold increase in the rate of antidepressant prescriptions in the educational group (P<0.05) and only 1.28-fold (P<0.05) and 1.34-fold (P<0.05) increase in control groups 1 and 2, respectively. However, the 12% decrease in suicide rate in the intervention regions was not significantly greater than the 4% decrease in the non-intervention region (P>0.05).
Our training program was beneficial for primary care physicians' ability to recognize and manage depression. However, there was no significant decrease in local suicide rates.
There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin ...reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene.
To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor).
The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project.
The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome.
The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.
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